CoCA — Aktiivsus-tähelepanuhäirega koosesinevad haigused ja tervisehäired / Comorbid Conditions of Attention Deficit/Hyperactive Disorders

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https://hdl.handle.net/10062/63786

CoCA kodulehekülg.

Psychiatric disorders are highly co-morbid, both with somatic and other mental disorders, and are one of the last areas of medicine where disease classifications are driven by phenomenology rather than pathophysiology. Here, we will study the comorbidity between the most frequent psychiatric conditions, attention-deficit/hyperactivity disorder (ADHD), mood and anxiety disorders, substance use disorders (SUD), and a highly prevalent somatic disorder, i.e. obesity. In this project, the CoCA consortium will:
• specify the population prevalence and sex-specificity of comorbidity of ADHD’s comorbidity with mood and anxiety disorders, SUD, and obesity across the lifespan (WP1)
• determine the socioeconomic impact of ADHD in conjunction with its common comorbid disorders (WP1)
• specify the genetic and environmental contributions to the overlap among the disorders (WP2)
• determine the biological mechanisms underlying ADHD and its comorbid disorders (mood and anxiety disorders, SUD, obesity) (WP2,3,4):
o Sleep and the circadian rhythm system (CIRCA system) (WP2,3)
o Reward processing system and dopaminergic neurotransmission therein (DA system) (WP2,4)
o Additional, currently unknown biological pathways derived from genetic big data studies (WP2)
• test biomarkers from candidate systems (CIRCA, DA) and identify novel ones (WP2,3,4)
• develop algorithms to predict the development of ADHD’s comorbidities based on epidemiological/genetic data as well as the CIRCA/DA systems (WP7)
• improve the diagnosis of ADHD-related comorbidity in adolescence / early adulthood through mobile healthcare (mHealth) approaches (WP5)
• develop an mHealth approach to support patients in daily life (mHealth-based monitoring and coaching) (WP5,6)
• establish effect sizes of non-pharmacologic treatments for ADHD with comorbid obesity and depression by targeting the CIRCA/DA systems with chronobiological approaches, physical exercise and mHealth-based coaching (WP6)
• explore targets for novel pharmacologic treatment strategies for ADHD and its comorbid disorders (WP8)
• disseminate results to the public, emphasizing the role of life-style modifications for prevention (WP9)
• educate and train a new generation of inter- and transdisciplinary researchers and clinicians (WP10)

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Driving risks of young drivers with symptoms of attention deficit hyperactivity disorder: association with the dopamine transporter gene VNTR polymorphism
(2022) Tokko, Tõnis; Eensoo, Diva; Miškinyte, Grete; Harro, Jaanus
Road traffic injuries are a leading cause of death for young adults, and young drivers with higher expression of symptoms of attention deficit-hyperactivity disorder (ADHD) could pose an even greater risk in traffic. Dopaminergic dysfunction has been found to occur in ADHD, with the dopamine transporter (DAT) gene VNTR polymorphism (DAT1 VNTR; rs28363170) being one of the most consistent genetic markers. Thus, we aimed at clarifying how the ADHD symptoms and the DAT1 VNTR relate to risk-taking behaviour in traffic, impulsivity and driving anger in young drivers. We used data of two traffic behaviour study samples (n = 741, mean age = 23.3±7.2 years; n = 995, mean age = 22.9±8.1 years) and the Estonian Children Personality Behaviour and Health Study (ECPBHS; traffic behaviour data n = 1016, mean age = 25.2±2.1 years). ADHD symptoms were assessed by self-report with the Adult ADHD Self-Report Scale (ASRS v1.1) and impulsivity with the Adaptive and Maladaptive Impulsivity Scale. Traffic behavioural measures were either self-reported (Driver Behaviour Questionnaire, Driving Anger Scale) or obtained from databases (registered accidents and violations). Drivers with more self-reported ADHD symptoms also reported more risk-taking in traffic and had more of recorded traffic accidents and violations. DAT1 9R carriers had a higher probability of high traffic risk behaviour only if they also had ADHD symptoms. Conclusion Higher level of ADHD symptoms is a significant risk factor in traffic, and carrying of the DAT1 9R allele appears to aggravate these risks.
Interactive effects of DRD2 rs6277 polymorphism, environment and sex on impulsivity in a population-representative study
(Elsevier, 2021-04) Klaus, K.; Vaht, M.; Pennington, K.; Harro, J.
Previous research has shown that dopaminergic dysregulation and early life stress interact to impact on aspects of impulse control. This study aimed to explore the potentially interactive effects of the rs6277 polymorphism of the dopamine D2 receptor gene (DRD2), stressful or supportive environment and sex on behavioural and self-reported measures of impulsivity, as well as alcohol use – a condition characterised by a deficit in impulse control. The sample consisted of the younger cohort (n=583) of the longitudinal Estonian Children Personality, Behaviour and Health Study. The results showed that the CC homozygotes (suggested to have decreased striatal D2 receptor availability) who had experienced stressful life events (SLE) or maltreatment in the family prior to age 15 showed higher self-reported maladaptive impulsivity at age 15. The genotype-SLE interaction and further association with sex was also evident in the frequency of alcohol use at age 15. Lack of warmth in the family contributed to significantly higher levels of thoughtlessness and more frequent alcohol use in CC carriers at age 25, whereas family support was associated with lower thoughtlessness scores in CC males, which may suggest a protective effect of supportive family environment in this group. Together the findings suggest that DRD2 rs6277 polymorphism, in interaction with environmental factors experienced in childhood and youth may affect facets of impulsivity. Future work should aim to further clarify the sex and age-specific effects of stressful and supportive environment on the development of neuronal systems that are compromised in disorders characterised by deficits in impulse control.
Variants of the aggression-related RBFOX1 gene in a population representative birth cohort study: aggressiveness, personality and alcohol use disorder
(2020) Vaht, Mariliis; Laas, Kariina; Fernàndez-Castillo, Noèlia; Kurrikoff, Triin; Kanarik, Margus; Faraone, Stephen V.; Tooding, Liina-Mai; Veidebaum, Toomas; Franke, Barbara; Reif, Andreas; Cormand, Bru; Harro, Jaanus
Background Recently RBFOX1, a gene encoding an RNA binding protein, has consistently been associated with aggressive and antisocial behaviour. Several loci in the gene have been nominally associated with aggression in genome-wide association studies; the risk alleles being more frequent in general population. We have hence examined the association of four RBFOX1 single nucleotide polymorphisms, previously found related to aggressive traits, with aggressiveness, personality, and alcohol use disorder in birth cohort representative samples. Methods We used both birth cohorts of the Estonian Children Personality Behaviour and Health Study (ECPBHS; original n=1,238). Aggressiveness was assessed using the Buss-Perry Aggression Questionnaire and the Lifetime History of Aggressiveness structured interview at age 25 (younger cohort) or 33 (older cohort). Big Five personality at age 25 was measured with self reports and the lifetime occurrence of alcohol use disorder assessed with the MINI interview. RBFOX1 polymorphisms rs809682, rs8062784, rs12921846 and rs6500744 were genotyped in all participants. Given the restricted size of the sample, correction for multiple comparisons was not applied. Results Aggressiveness was not significantly associated with RBFOX1 genotype. RBFOX1 rs8062784 was associated with neuroticism and rs809682 with extraversion. Two out of four analyzed RBFOX1 variants, rs8062784, and rs12921846, were associated with occurrence of alcohol use disorder. Conclusions In the birth cohort representative sample of the ECPBHS, no association of RBFOX1 with aggressiveness was found, but RBFOX1 variants affected basic personality traits and the prevalence of alcohol use disorder. Future studies on RBFOX1 should consider the moderating role of personality and alcohol use patterns in aggressiveness.
Neuropeptide Y gene variants in obesity, dietary intake, blood pressure, lipid and glucose metabolism: a longitudinal birth cohort study
(Elsevier, 2021) Katus, Urmeli; Villa, Inga; Ringmets, Inge; Veidebaum, Toomas; Harro, Jaanus
Objective: Neuropeptide Y affects several physiological functions, notably appetite regulation. We analysed the association between four single nucleotide polymorphisms (SNP) in the NPY gene (rs5574, rs16147, rs16139, rs17149106) and measures of obesity, dietary intake, physical activity, blood pressure, glucose and lipid metabolism from adolescence to young adulthood. Methods: The sample included both birth cohorts of the Estonian Children Personality Behaviour and Health Study at ages 15 (n = 1075 with available complete data), 18 (n = 913) and 25 (n = 926) years. Linear mixed-effects regression models were used for longitudinal association between NPY SNP-s and variables of interest. Associations at ages 15, 18 and 25 were analysed by ANOVA. Results: Rs5574 CC-homozygotes had a greater increase per year in waist-to-hip ratio (WHR) and a smaller decrease in daily energy intake and carbohydrate intake from age 15 to 25 years; fasting glucose and cholesterol were higher in rs5574 CC-homozygotes. Rs16147 TT homozygotes had higher body weight and a greater increase in sum of 5 skinfolds, waist circumference, WHR and waist-to-height ratio; however, they had lower carbohydrate intake throughout the observation period. Rs16147 TT-homozygotes and both rs16139 and rs17149106 heterozygotes had higher triglyceride levels. All NPY SNP-s were associated with blood pressure: rs5574 TT-and rs16147 CC-homozygotes had a smaller increase in diastolic blood pressure, while rs16139 and rs17149106 heterozygous had lower blood pressure throughout the study. Conclusion: Variants of the NPY gene were associated with measures of obesity, dietary intake, glucose and lipid metabolism and blood pressure from adolescence to young adulthood.
Low cardiorespiratory fitness and obesity for ADHD in childhood and adolescence: A 6‐year cohort study
(2020-12-20) Muntaner Mas, Adrià; Ortega, Francisco B.; Femia, Pedro; Kiive, Evelyn; Evelyn, Diva; Mäestu, Jarek; Franke, Barbara; Reif, Andreas; Faraone, Stephen V.; Harro, Jaanus
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent disorder in childhood and identifying risk factors associated with developing ADHD during childhood and adolescence is relevant from a clinical and epidemiological point of view. This work examines (1) whether overweight/obesity and low cardiorespiratory fitness (CRF) are associated with increased ADHD symptoms in childhood (cross sectional analysis), and (2) whether overweight/obesity and low CRF levels during childhood predict increased ADHD symptoms in adolescence (longitudinal analysis). Data were examined from a longitudinal study of Estonian inhabitants who took part in the European Youth Heart Study (EYHS) in 1998 and 1999 (baseline age 9 years), who were re-evaluated 6 years later as part of the longitudinal Estonian Children Personality Behaviour and Health Study (ECPBHS). CRF was determined via an incremental maximal cycle-ergometer test, overweight/obesity was based on body mass index (BMI), and the 7-point af Klinteberg Hyperactivity Scale was used to assess ADHD symptoms at both time points. In the cross-sectional analysis, children with overweight/obesity were at greater risk of ADHD symptoms compared to underweight/normal-weight children, as were those unfit compared to fit children (OR=1.92 and 95%CI=1.02–3.55, and OR=1.84 and 95%CI=1.13–2.98, respectively). The cross-sectional association between BMI and ADHD symptoms was mediated by CRF (z=2.116, 42.9%; p=0.034). The longitudinal analysis showed being unfit in childhood was associated with a greater risk of increased ADHD symptoms 6 years later in adolescence (OR=2.26 and 95%CI=1.14–4.47), even after adjusting for baseline ADHD symptoms and BMI. Our result suggests that being unfit is an additional risk factor for increased ADHD symptoms during childhood and adolescence. The association between BMI and ADHD symptoms was mediated by CRF in the cross-sectional analysis and no association was seen between overweight/obesity and increased ADHD symptoms.
Association of orexin/hypocretin receptor gene (HCRTR1) with reward sensitivity, and interaction with gender
(Elsevier, 2020) Pulver, Aleksander; Kiive, Evelyn; Harro, Jaanus; Kanarik, Margus
Orexins/hypocretins maintain wakefulness, increase appetite and participate in the coordination of stress response. We have recently provided evidence on the role of orexins in aggression, showing the association of the HCRTR1 genotype. (rs2271933 G > A; leading to amino acid substitution Ile408Val) with aggressiveness or breach of law in four independent cohorts. Aggressive behaviour can be reward driven and hence we have examined the association of HCRTR1 rs2271933 genotype with different aspects of reward sensitivity in the birth cohort representative Estonian Children Personality Behaviour and Health Study. HCRTR1 genotype was associated with reward sensitivity in a gender dependent manner. Male HCRTR1 A/A homozygotes had higher Openness to Rewards and the overall reward sensitivity score while, in contrast, female A/A homozygotes scored lower than G-allele carriers in Openness to Rewards. In the total sample, aggressiveness correlated positively with reward sensitivity, but this was on account of Insatiability by Reward. In contrast, the HCRTR1 A/A homozygotes had a positive association of aggressiveness and Openness to Rewards. Experience of stressful life events had a small but significant increasing effect on both aspects of reward sensitivity, and correlated in an anomalous way with reward sensitivity in the HCRTR1 A/A homozygotes. Conclusively, the higher aggressiveness of HCRTR1 A/A homozygotes appears based on a qualitative difference in sensitivity to rewards, in the form that suggests their lower ability to prevent responses to challenges being converted into overt aggression.
The role of reward sensitivity in obesity and its association with Transcription Factor AP2B: a longitudinal birth cohort study
(Elsevier, 2020) Katus, Urmeli; Villa, Inga; Ringmets, Inge; Pulver, Aleksander; Veidebaum, Toomas; Harro, Jaanus
Objective One factor potentially contributing to obesity is reward sensitivity. We investigated the association between reward sensitivity and measures of obesity from 9–33 years of age, paying attention to the inner structure of reward sensitivity. Methods The sample included both birth cohorts (originally n = 1176) of the Estonian Children Personality Behaviour and Health Study. The association between reward sensitivity and measures of obesity was assessed using mixed-effects regression models. Associations at ages 9 (younger cohort only), 15, 18, 25 and 33 (older cohort) years were analyzed by one-way ANOVA. The indirect effect of the gene encoding transcription factor 2 beta (TFAP2B) on obesity through reward sensitivity was tested using mediation analysis. Results According to linear mixed effects regression models, an increase in scores of Insatiability by Reward and both of its components, Excessive Spending and Giving in to Cravings, significantly increased body weight, body mass index, sum of five skinfolds, waist circumference, hip circumference and waist-to-height ratio from 15 to 25 years of age. Findings were similar at age 9 and 33 years. In contrast, no association between obesity and Openness to Rewards or its facets was observed. The TFAP2B genotype was also associated with fixation to rewards in females, but not with striving towards reward multiplicity. Conclusion Our results suggest that reward sensitivity is associated with obesity by its reward fixation component. The heterogeneity of the reward sensitivity construct should be taken into account in studies on body composition.
Reward sensitivity, affective neuroscience personality, symptoms of attentiondeficit/hyperactivity disorder, and TPH2-703G/T (rs4570625) genotype
(Cambridge University Press, 2020) Pulver, Aleksander; Kiive, Evelyn; Harro, Jaanus
Objective: Reward sensitivity is an increasingly used construct in psychiatry, yet its possible inner structure and relationship with other affective variables are not well known. Methods: A reward sensitivity measurement scale was constructed on the basis of large item pool collected from birth cohort representative samples (the Estonian Children Personality Behaviour and Health Study; original n = 1238). Affective Neuroscience Personality Scale (ANPS) and the Adult Attention deficit hyperactivity disorder (ADHD) Self-Report Scale (ASRS) were administered in young adulthood. A variant (rs4570625) of the gene encoding tryptophan hydroxylase 2 (TPH2) that is responsible for the synthesis of central serotonin was genotyped. Results: Reward sensitivity consisted of two orthogonal components, operationally defined as Openness to Rewards and Insatiability by Reward, that respectively characterise the striving towards multiple rewards and the strong pursuit and fixation to a particular reward. While SEEKING and PLAY (and to lower extent CARE) of the ANPS co-varied with Openness to Rewards, FEAR, SADNESS, and ANGER were related to Insatiability by Reward. The total score of ASRS was moderately correlated with Insatiability by Reward, while the association with Openness to Rewards was negligible. However, ASRS Inattention had some negative relationship with the Social Experience facet of Openness to Rewards. The T/T homozygotes for the TPH2 promoter polymorphism had lower Insatiability by Reward but not Openness to Rewards. Conclusions: Behaviours sensitive to rewards are separable to the components of variability and fixation, and these components are differentially related to affective aspects of personality, attention, and hyperactivity as well as to TPH2 genotype.
RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior
(Eur Neuropsychopharmacol., 2020) Fernàndez-Castillo, Noèlia; Gan, Gabriela; M.J. van Donkelaar, Marjolein; Vaht, Mariliis; Weber, Heike; Retz, Wolfgang; Meyer-Lindenberg, Andreas; Franke, Barbara; Harro, Jaanus; Reif, Andreas; Faraone, Stephen V.; Cormand, Bru
The RBFOX1 gene (or A2BP1) encodes a splicing factor important for neuronal development that has been related to autism spectrum disorder and other neurodevelopmental phenotypes. Evidence from complementary sources suggests that this gene contributes to aggressive behavior. Suggestive associations with RBFOX1 have been identified in genome-wide association studies (GWAS) of anger, conduct disorder, and aggressive behavior. Nominal association signals in RBFOX1 were also found in an epigenome-wide association study (EWAS) of aggressive behavior. Also, variants in this gene affect temporal lobe volume, a brain area that is altered in several aggression-related phenotypes. In animals, this gene has been shown to modulate aggressive behavior in Drosophila. RBFOX1 has also been associated with canine aggression and is upregulated in mice that show increased aggression after frustration of an expected reward. Associated common genetic variants as well as rare duplications and deletions affecting RBFOX1 have been identified in several psychiatric and neurodevelopmental disorders that are often comorbid with aggressive behaviors. In this paper, we comprehensively review the cumulative evidence linking RBFOX1 to aggression behavior and provide new results implicating RBFOX1 in this phenotype. Most of these studies (genetic and epigenetic analyses in humans, neuroimaging genetics, gene expression and animal models) are hypothesis-free, which strengthens the validity of the findings, although all the evidence is nominal and should therefore be taken with caution. Further studies are required to clarify in detail the role of this gene in this complex phenotype.
Nice guys: Homozygocity for the TPH2 -703G/T (rs4570625) minor allele promotes low aggressiveness and low anxiety
(2017) Laas, Kariina; Kiive, Evelyn; Mäestu, Jarek; Vaht, Mariliis; Veidebaum, Toomas; Harro, Jaanus
Background: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. We examined whether the TPH2 polymorphism -703G/T (rs4570625) is associated with aggressiveness and impulsivity, and the prevalence of psychiatric disorders, in a population-representative sample. Methods: We used self and proxy reports on aggressive behaviour in the younger birth cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study collected at age 25, and earlier collected impulsivity and related data of both ECPBHS cohorts. Results: The TT homozygous males reported less aggressive behaviour in the Life History of Aggression interview at age 25. They also had significantly lower scores in Illinois Bully Scale peer reports, and less ADHD symptoms rated by teachers both at ages 9 and 15. The TT homozygotes of both sexes had the lowest Maladaptive Impulsivity at ages 18 and 25, and the highest Adaptive Impulsivity at age 25. The TT homozygotes also had low depressiveness and trait anxiety by age 25, and the odds ratio for the prevalence of anxiety disorders was 9.38 for the G-allele carriers. Limitations: The main limitation of the study is the naturally occurring low number of subjects with the TT genotype. Conclusions: Subjects with the TPH2 rs4570625 TT genotype, especially males, exhibit less aggression and a favourable impulsivity profile, and develop anxiety disorders by young adulthood less often.
Association of FTO rs1421085 with obesity, diet, physical activity and socioeconomic status: a longitudinal birth cohort study
(2020) Katus, Urmeli; Villa, Inga; Ringmets, Inge; Vaht, Mariliis; Mäestu, Evelin; Mäestu, Jarek; Veidebaum, Toomas; Harro, Jaanus
Background and aims Fat mass and obesity-associated protein (FTO) variants are among genetic variants frequently associated with obesity. We analyzed the association between FTO rs1421085 polymorphism and obesity, dietary intake, cardiorespiratory fitness (CRF), physical activity, and socioeconomic status (SES) from the age of 9–25 years. Methods and results The sample included both birth cohorts (originally n = 1176) of the Estonian Children Personality Behaviour and Health Study. The association between FTO rs1421085 and obesity, dietary intake, CRF, physical activity, and SES from the age of 15–25 years was assessed using linear mixed-effects regression models. Associations at ages 9 (younger cohort only), 15, 18, and 25 years were assessed by one-way ANOVA. Male C-allele carriers had significantly (p < 0.05) higher body mass index (BMI), sum of 5 skinfolds, body fat percentage, and hip circumference from the age of 15–25 years. Findings were similar at the age of 9 years. In female subjects, waist-to-hip ratio was significantly greater in CC homozygotes. Interestingly, female CC homozygotes had a greater decrease in the rate of change in daily energy intake and lipid intake per year and higher physical activity score at every fixed time point. Moreover, in females, an effect of FTO × SES interaction on measures of obesity was observed. Conclusion The FTO rs1421085 polymorphism was associated with obesity and abdominal obesity from childhood to young adulthood in males, and with abdominal obesity from adolescence to young adulthood in females. This association is rather related to differences in adipocyte energy metabolism than lifestyle.
Low cholesterol levels in children predict impulsivity in young adulthood
(2019) Tomson-Johanson, Katrin; Kaart, Tanel; Kiivet, Raul-Allan; Veidebaum, Toomas; Harro, Jaanus
Objective: Severe behavioural issues such as impulsive action and suicide have since long been associated with low levels of cholesterol. While it is known that cholesterol plays a role in neural development and hence low levels of serum lipids could have long-term effects on behaviour, there are no longitudinal studies showing association of serum lipids levels with impulsivity. We aimed to examine the prognostic properties of serum lipid levels during childhood and adolescence on measures of impulsivity during early adulthood in a representative birth cohort sample. Methods: We have investigated whether serum lipid levels measured at 9, 15, 18 and 25 years of age have an association with impulsivity in 25 years old young adults. This analysis was based on data of the birth cohort representative samples of the Estonian Children Personality Behaviour and Health Study (original n=1238). Impulsivity was self-reported with the Adaptive and Maladaptive Impulsivity Scale. Results: Total and LDL cholesterol measured in 9, 15 and 18 years old boys predicted Disinhibition and Thoughtlessness in 25 years old young adults. High scores of Disinhibition were associated with low total and LDL cholesterol levels in males but, while less consistently, with high total and LDL cholesterol levels in females. Cross-sectional analysis did not result in systematic outcomes. Conclusions: Serum lipid levels could have an impact on development of maladaptive impulsivity starting from an early age. This effect of cholesterol continues throughout adolescence into young adulthood.
Association of the COMT Val108/158Met genotype with professional career and education: The Val-allele is more frequent in managers and in enterprising occupations
(ScienceDirect, 2018-01) Kurrikoff, Triin; Kaarma, Katrin; Tooding, Liina-Mai; Vaht, Mariliis; Tulviste, Tiia; Veidebaum, Toomas; Harro, Jaanus
Catechol-O-methyl transferase (COMT) is a key player in neurotransmission by catecholamines, and the functional COMT Val108/158Met polymorphism is strongly related to prefrontal reactivity and to dopamine levels. As dopamine is a critically important neurotransmitter in cognition, emotion and motivation, we addressed the potential impact of this genotype on life course by examining its association with being in enterprising professions. The parents (n = 1410) of the target subjects in the Estonian Children Personality Behaviour and Health Study reported their current occupation, and those classified as enterprising (n = 197; 18%) were compared with the remaining group. Additionally, the subjects self-classified themselves according to the International Standard Classification of Occupations and the group of managers (6.2%) was compared to other groups. We found that the COMT Val108/158Met Val/Val homozygotes were overrepresented among enterprising occupations and the Val-allele carriers among self-classified managers. While several measures associated with the Val/Val homozygosity were also associated with enterprising occupation, no simple path from the genotype to enterprising occupations emerged from structural equation models, suggesting that the COMT Val108/158Met genotype contributes to choices of profession via multiple interactive features. We also reproduced a previous finding that the COMT genotype is associated with educational attainment in a gender-dependent manner.
Orexin/hypocretin receptor gene (HCRTR1) variation is associated with aggressive behaviour
(ScienceDirect, 2019-09) Harro, Jaanus; Laas, Kariina; Eensoo, Diva; Kurrikoff, Triin; Sakala, Katre; Vaht, Mariliis; Parik, Jüri; Mäestu, Jarek; Veidebaum, Toomas
Orexins, alternatively called hypocretins, are neuropeptides with crucial role in maintaining wakefulness. The orexin system is thought to mediate a coordinated defense response but thus far investigated from the flight, but never fight, response perspective. An HCRTR1 gene variant (rs2271933 G > A) leading to amino acid substitution (Ile408Val) has been associated with migraine and mood disorders. We genotyped, and assessed aggressive behaviour in both birth cohorts (n = 655 and 583) of the Estonian Children Personality Behaviour and Health Study (ECPBHS). Measures of aggressiveness were collected at age 25 or 33 and data on stressful life events (SLE-s) at age 15. Violations of traffic law were monitored in the samples of the Estonian Psychobiological Study of Traffic Behaviour. In both birth cohorts of the ECPBHS, the HCRTR1 the A/A homozygotes reported higher aggression in both Buss-Perry Aggression Questionnaire and the Life History of Aggression Interview. With either measure of aggressiveness, the HCRTR1 genotype effect was dependent on experience of SLE, the highest level of aggressiveness increase by environment being found in female A/A homozygotes. The HCRTR1 A/A homozygotes scored higher in the ANGER facet of the Affective Neuroscience Personality Scale, while such an effect on FEAR was found only in females. Male HCRTR1 A/A homozygotes were more likely to relapse into drunk driving of a passenger car, and in two independent samples the A-allele carriers were causing traffic accidents more often. Conclusively, self-report, interview, and traffic record data converge indicating that the HCRTR1 Ile408Val genotype is associated with aggressiveness and breach of law. This article is part of the Special Issue entitled ‘Current status of the neurobiology of aggression and impulsivity’.
Efficacy of intervention at traffic schools reducing impulsive action, and association with candidate gene variants
(Acta Neuropsychiatrica, 2019) Luht, Kadi; Tokko, Tõnis; Eensoo, Diva; Vaht, Mariliis; Harro, Jaanus
OBJECTIVE: Road traffic injuries are the leading cause of death among young people. Recognition of the contribution of impulsive behaviour may help novice drivers to behave more safely. Previously a brief intervention focusing on impulsive traffic behaviour conducted by psychologists in driving schools had been effective. The aim of this study was an independent re-evaluation of the effect of the intervention, as conducted by driving school teachers, and assessment of the potential associations with candidate genotypes. METHODS: Driving school students (mean age 22.5, SD=7.9) were divided into intervention (n=704) and control (n=737) groups. Driving school teachers were trained to administer the intervention which consisted of a lecture and group work (1.5 h in total) on impulsivity. Traffic offences and crashes were monitored during 3 years, using police and traffic insurance fund databases. Functional polymorphisms of the dopamine transporter (DAT) and serotonin transporter genes (DAT1 VNTR and 5-HTTLPR) were assessed. RESULTS: The intervention significantly lowered general traffic risk and prevalence of traffic accidents. DAT1 VNTR 9R carriers, particularly males, had higher general traffic risk in the whole sample. Female 5-HTTLPR s' allele carriers of the intervention group had the lowest general traffic risk. Intervention was most effective in female DAT1 VNTR 10R/10R homozygotes. CONCLUSIONS: Brief impulsivity-centred intervention appears as a promising strategy for preventing risk-taking behaviour in novice drivers and can be fully integrated to driving school curriculum.
Relapse of drunk driving and association with traffic accidents, alcohol-related problems, and biomarkers of impulsivity
(Cambridge University Press, 2018) Tokko, Tõnis; Eensoo, Diva; Vaht, Mariliis; Lesch, Klaus-Peter; Reif, Andreas; Harro, Jaanus
Objective: Individual biological predispositions should play a role in risky driving behaviour. Platelet monoamine oxidase (MAO) activity, dopamine transporter gene (DAT1) and neuropeptide S receptor 1 (NPSR1) gene polymorphisms have been identified as markers of impulsivity, alcohol use and excessive risk-taking. We aimed to find out how this knowledge on neurobiology of impulsivity applies to drunk driving and traffic behaviour in general. Methods: We have longitudinally examined the behaviour of drunk drivers (n=203) and controls (n=211) in traffic, in association with their alcohol-related problems, personality measures and the three biomarkers. We analysed differences between the subjects based on whether they had committed driving while impaired by alcohol (DWI) violation in a 10-year time period after recruitment or not and investigated further, what kind of predictive value do the different biomarkers have in committing DWI and other traffic violations and accidents. Results: The original drunk drivers group had lower platelet MAO activity but further DWI was not significantly associated with this measure. Being a NPSR1 T-allele carrier contributed to the risk of repeatedly committing DWI. DAT1 9R carriers in contrast were involved in more traffic accidents by their own fault (active accidents), compared to 10R homozygotes in the whole sample. All groups with DWI also had significantly more alcohol-related problems and higher scores in maladaptive impulsivity compared to controls without DWI. Conclusions: Established biological markers of alcohol use and impulsivity can be reliably associated with everyday traffic behaviour and help in contributing to the understanding of the need for more personalized prevention activities.
Association between Transcription Factor AP-2B genotype, obesity, insulin resistance and dietary intake in a longitudinal birth cohort study Transcription Factor AP-2B associated with obesity
(Springer Nature, 2019) Joost, U.; Harro, J.; Veidebaum, L.; Oreland, L.; Comasco, E.; Villa, I.
The development of obesity has a large genetic component, and the gene encoding the transcription factor 2 beta (TFAP2B) has been identified as one of the responsible factors. We investigated the effect of TFAP2B intron 2 variable number tandem repeat (VNTR) genotype on obesity, insulin resistance and dietary intake from 15 to 33 years of age.

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